Ventricular Remodeling In Rats Research Articles

Kidney-tonifying blood-activating decoction delays ventricular remodeling in rats with chronic heart failure by regulating gut microbiota and metabolites and p38 mitogen-activated protein kinase/p65 nuclear factor kappa-B/aquaporin-4 signaling pathway

Ethnopharmacological relevanceMyocardial infarction has likely contributed to the increased prevalence of heart failure(HF).As a result of ventricular remodeling and reduced cardiac function, colonic blood flow decreases, causing mucosal ischemia and hypoxia of the villous structure of the intestinal wall.This damage in gut barrier function increases bowel wall permeability, leading to fluid metabolism disorder,gut microbial dysbiosis, increased gut bacteria translocation into the circulatory system and increased circulating endotoxins, thus promoting a typical inflammatory state.Traditional Chinese Medicine plays a key role in the prevention and treatment of HF.Kidney-tonifying Blood-activating(KTBA) decoction has been proved for clinical treatment of chronic HF.However,the mechanism of KTBA decoction on chronic HF is still unclear. Aims of the studyThe effect of KTBA decoction on gut microbiota and metabolites and p38MAPK/p65NF-κB/AQP4 signaling in rat colon was studied to investigate the mechanism that KTBA decoction delays ventricular remodeling and regulates water metabolism disorder in rats with HF after myocardial infarction based on the theory of "Kidney Storing Essence and Conducting Water". Material and methodsIn vivo,a rat model of HF after myocardial infarction was prepared by ligating the left anterior descending coronary artery combined with exhaustive swimming and starvation.The successful modeling rats were randomly divided into five groups:model group, tolvaptan group(gavaged 1.35mg/(kg•D) tolvaptan),KTBA decoction group(gavaged 15.75g/(kg•D) of KTBA decoction),KTBA decoction combined with SB203580(p38MAPK inhibitor) group(gavaged 15.75g/(kg•D) of KTBA decoction and intraperitoneally injected 1.5mg/(kg•D) of SB203580),and KTBA decoction combined with PDTC(p65NF-kB inhibitor) group(gavaged 15.75g/(kg•D) of KTBA decoction and intraperitoneally injected 120mg/(kg•D) of PDTC).The sham-operation group and model group were gavaged equal volume of normal saline.After 4 weeks of intervention with KTBA decoction,the effect of KTBA decoction on the cardiac structure and function of chronic HF model rats was observed by ultrasonic cardiogram.General state and cardiac index in rats were evaluated.Enzyme linked immunosorbent assay(ELISA) was used to measure N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in rat serum.Hematoxylin and eosin(H&E) staining,and transmission electron microscope(TEM) were used to observe the morphology and ultrastructure of myocardial and colonic tissue,and myocardial fibrosis was measured by Masson's staining.Cardiac E-cadherin level was detected by Western blot.The mRNA expression and protein expression levels of p38MAPK,I-κBα, p65NF-κB,AQP4,Occludin and ZO-1 in colonic tissue were detected by reverse transcription-quantitative real-time polymerase chain reaction(RT-qPCR) and immunohistochemistry. Protein expression of p38MAPK, p-p38MAPK,I-κBα,p-I-κBα,p65NF-κB, p-p65NF-κB,AQP4,Occludin and ZO-1 in rat colon was detected using Western blot.Colonic microbiota and serum metabolites were respectively analyzed by amplicon sequencing and liquid chromatography-mass spectrometry.In vitro, CCD-841CoN cell was placed in the ischemic solution under hypoxic conditions (94%N2,5%CO2,and 1%O2) in a 37 °C incubator to establish an ischemia and hypoxia model.The CCD-841CoN cells were divided into 7 groups, namely blank group and model group with normal rat serum plus control siRNA, tolvaptan group with rat serum containing tolvaptan plus control siRNA, KTBA group with rat serum containing KTBA plus control siRNA, KTBA plus p38MAPK siRNA group, KTBA plus p65NF-κB siRNA group,and KTBA plus AQP4siRNA group.After 24h and 48h of intervention with KTBA decoction,RT-qPCR,immunofluorescence and Western blot was used to detect the mRNA expression and protein expression levels of p38MAPK,I-κBα,p65NF-κB,AQP4, Occludin and ZO-1 in CCD-841CoN cells. ResultsCompared with the model, KTBA decoction improved the general state, decraesed the serum NT-proBNP level,HW/BW ratio, LVIDd and LVIDs, increased E-cadherin level,EF and FS,reduced number of collagen fibers deposited in the myocardial interstitium,and recovered irregular arrangement of myofibril and swollen or vacuolated mitochondria with broken crista in myocardium.Moreover, KTBA decoction inhibited the expression of p38MAPK,I-κBα,and p65NF-κB and upregulated AQP4, Occludin and ZO-1 in colon tissues and CCD-841CoN cells.Additionally,p38siRNA or SB203580, p65siRNA or PDTC, and AQP4siRNA partially weakened the protective effects of KTBA in vitro and vivo.Notably,The LEfSe analysis results showed that there were six gut biomaker bacteria in model group, including Allobaculum, Bacillales,Turicibacter, Turicibacterales,Turicibacteraceae,and Bacilli. Besides, three gut biomaker bacteria containing Deltaproteobacteria, Desulfovibrionaceae,and Desulfovibrionales were enriched by KTBA treatment in chronic HF model.There were five differential metabolites, including L-Leucine,Pelargonic acid, Capsidiol,beta-Carotene,and L- Erythrulose, which can be regulated back in the same changed metabolic routes by the intervention of KTBA.L-Leucine had the positive correlation with Bacillales, Turicibacterales,Turicibacteraceae,and Turicibacter.L-Leucine significantly impacts Protein digestion and absorption, Mineral absorption,and Central carbon metabolism in cancer regulated by KTBA, which is involved in the expression of MAPK and tight junction in intestinal epithelial cells. ConclusionsKTBA decoction manipulates the expression of several key proteins in the p38MAPK/p65NF-κB/AQP4 signaling pathway, modulates gut microbiota and metabolites toward a more favorable profile, improves gut barrier function, delays cardiomyocyte hypertrophy and fibrosis,and improves cardiac function.

Icariin improves cardiac function and remodeling via the TGF-β1/Smad signaling pathway in rats following myocardial infarction

BackgroundPostinfarction cardiac remodeling presents a compensatory mechanism aimed at mitigating congestive heart failure. It is distinguished by progressive dilatation and hypertrophy of the ventricular chambers, fibrotic alterations, and prolonged apoptosis of cardiomyocytes. The primary objective of this study was to assess the effects of icariin on myocardial fibrosis and ventricular remodeling in rats subjected to myocardial infarction (MI).MethodsMale Sprague‒Dawley (SD) rats were subjected to randomization and subsequently divided into distinct groups: the control group, the sham group (undergoing sham operation), the MI group (experiencing ligation of the left anterior descending artery), and the icariin group. Within the icariin group, rats were further categorized into three different dose groups based on the administered icariin dosage: the MI30 group (30 mg/kg/day), the MI60 group (60 mg/kg/day), and the MI120 group (120 mg/kg/day). Cardiac function evaluation was carried out using echocardiography. Histological examinations, including hematoxylin and eosin (HE) staining, Masson staining, and immunohistochemistry studies, were conducted 90 days after the occurrence of MI. Additionally, Western blotting was employed to assess TGF‐β1, p-Smad2, and p-Smad3 levels.ResultsThe administration of icariin revealed a noteworthy enhancement in cardiac function among rats afflicted with left anterior descending coronary artery (LAD) ligation. In comparison to the icariin groups, the MI group exhibited reduced EF and FS, along with elevated LVEDD and LVESD. Furthermore, the cardiac fibrosis levels in the MI group rats exhibited a considerable increase compared to those in the icariin group. Notably, the levels of Collagen I, Collagen III, MMP2, and MMP9 were significantly higher in the MI group than in the icariin group, with evident distinctions. Moreover, the expression levels of TGF-β, IL-13, p-Smad2, and p-Smad3 were notably upregulated in the MI group compared to the icariin group.ConclusionsIn an experimental rat model of MI, the administration of icariin resulted in the amelioration of both cardiac function and remodeling processes, operating through the intricate TGF-β1/Smad signaling pathway.

Investigating the Effects and Mechanism of Rhodiola Rosea Injection on Cardiac Function in Rats with Chronic Heart Failure.

To study the effect of Rhodiola Rosea injection on cardiac function and the reninangiotensin- aldosterone system (RASS) in rats with chronic heart failure. Rhodiola Rosea injection, a traditional Chinese medication for relieving blood stasis and improving blood circulation, is an excellent therapeutic for treating coronary heart disease-angina pectoris. Rhodiola Rosea injection's major component, salidroside, protects the cardiovascular system. But there isn't much first-hand evidence about how injectable Rhodiola Rosea affects heart failure. In this study, a rat model of heart failure was established, and the effect of Rhodiola rosea injection on myocardial cell morphology, cardiac function, and ventricular remodelling in rats with heart failure was investigated. 66 SD male rats were selected; 10 were randomly selected as a blank control group, and 56 were treated intraperitoneally with doxorubicin (4 g/g). After 6 weeks, all animals had LVEF 60%. Established a heart failure model. Each group had 14 rats: model control, low-dose, mediumdose, and high-dose Rhodiola Rosea injection. The 2 mL/kg of Rhodiola Rosea injection was injected into the tail vein once a day for 2 weeks. Both the blank and control groups received normal daily saline. After 2 weeks, the echocardiographic index, RASS-related index, and serum BNP level were assessed in all rats, and myocardial tissue morphology was observed. MiRNA423-5p, miRNA499-5p, and miRNA210-3p were extracted from peripheral blood. Rhodiola rosea injection on its expression was compared to healthy control rats. 6 mL/kg Rhodiola Rosea injection lowered LVEDV and LVESV while increasing LVEF and LVFS. Injections of 6 mL/kg Rhodiola Rosea reduce plasma levels of miR-210-3p, miR-423- 5p, miRNA-499, and BNP in heart failure model rats. The 6 mL/kg Rhodiola Rosea injection can restore the RASS indexes of heart failure rats to the level of the normal group. The present study offers preliminary evidence supporting the use of Rhodiola Rosea injection in the treatment of heart failure and offers a solid foundation for clinical off-label medication use.

Linggui Zhugan decoction delays ventricular remodeling in rats with chronic heart failure after myocardial infarction through the Wnt/β-catenin signaling pathway

ContextTraditional Chinese medicine plays an important role in the prevention and treatment of heart failure (HF). Linggui Zhugan decoction has been approved for clinical treatment of chronic HF. However, the mechanism is still unclear. ObjectiveThe effect of Linggui Zhugan decoction on the Wnt/β-catenin signaling pathway in rat myocardium was studied to investigate the mechanism by Linggui Zhugan decoction effects ventricular remodeling in rats with heart failure after myocardial infarction. MethodA rat model of HF after myocardial infarction was prepared by ligating the left anterior descending coronary artery. After 6 weeks of intervention with Linggui Zhugan decoction, the effect of Linggui Zhugan decoction on the cardiac function of chronic HF model rats was observed. Myocardial infarct size was measured by triphenyl tetrazolium chloride (TTC) staining. Enzyme linked immunosorbent assays (ELISAs) were used to measure NT-proBNP and sST-2 concentrations in rat serum. Hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were used to observe the morphology of myocardial tissue; immunohistochemistry was used to detect the protein expression of type I collagen and type III collagen in myocardial tissue; and mRNA expression levels of Wnt3a, GSK-3β, β-catenin, and c-Myc in the infarct marginal zone were detected using PCR. Protein expression of Wnt3a, p-GSK-3β, GSK-3β, and β-catenin in the infarct marginal zone was detected using western blot. ResultsCompared with the control, Linggui Zhugan decoction reduced the levels of serum ST-2 and NT-proBNP, improved cardiac function, and reduced the deposition of collagen fiber. In addition, Linggui Zhugan decoction inhibited the expression of Wnt3a, p-GSK-3β, and β-catenin in cardiomyocytes. ConclusionLinggui Zhugan decoction inhibits the expression of several key proteins in the Wnt/β-catenin signaling pathway, delays cardiomyocyte hypertrophy and fibrosis, and improves cardiac function.

Fuyu Decoction improves ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR pathway-mediated autophagy

To investigate the effect of Fuyu Decoction on ventricular remodeling and its association with AMPK/mTOR pathway-mediated autophagy in rats with heart failure. Thirty male Wistar rat models of heart failure induced by ligation of the left anterior descending coronary artery were divided into model group, Fuyu Decoction treatment group, Fuyu Decoction treatment +AMPK agonist group (n=10), with another 10 rats receiving sham operation as the Sham group. After 8 weeks of drug intervention, the changes of ventricular function and ventricular remodeling indexs of the rats were assessed. TTC staining was used to detect the myocardial infarction area, and HE and Masson staining were used to observe the pathological changes in the myocardial tissue. Western blotting was performed to detect the protein expressions of p-AMPK, p-mTOR, LC3-II, Beclin1 and p62 in the myocardial tissue. Compared with the sham-operated rats, the rat models of heart failure showed significantly increased left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), and left ventricular mass index (LVMI) (P < 0.01), reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and decreased spherical index (SI) were (P < 0.01). The rat models also showed increased myocardial infarction area, obvious myocardial pathologies and fibrosis, increased apoptosis rate of the cardiomyocytes, enhanced myocardial expressions of p-AMPK, LC3-II/LC3-I and Beclin1 (P < 0.01), and reduced expressions of p-mTOR and p62 (P < 0.01). Fuyu Decoction treatment significantly ameliorated these changes in the rat models (all P < 0.01), but its effects were obviously blocked by treatment with EX229. Fuyu Decoction can improve ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR signaling-mediated autophagy in the cardiomyocytes.

Ameliorative Effects of Cang-ai Volatile Oil on Left Ventricular Remodeling in Rats

To evaluate with 7T cardiac magnetic resonance tissue tracking imaging (CMR-TT) the ameliorative effect of Cang-ai volatile oil (CAVO) on left ventricular remodeling (LVR) in rats induced by isoproterenol (ISO), and to make preliminary investigation into CAVO's effects on endothelial dysfunction in LVR. A total of 35 healthy male Sprague-Dawley (SD) rats were randomly assigned to two groups, the experimental group ( n=27) and the normal control group ( n=8). The rat model of LVR was established by subcutaneous injection of ISO solution at 10 mg·kg -1·d -1 at multiple sites for 10 consecutive days. After modeling was completed, the surviving rats ( n=24) in the experimental group were then randomly assigned to the blank experimental group, CAVO group, and Shexiang Baoxin pill (SXBXP) group ( n=8 in each group). Rats in each group were given via gavage the corresponding intervention medicine or an equivalent amount of normal saline solution for 28 consecutive days. At the end of modeling and intragastric intervention, 7T CMR cine sequence scanning was conducted to collect data. Then, post-processing software CVI42 was used to analyze the images and to compare and contrast the changes in the parameters of left ventricular cardiac function and myocardial strain in each group before and after the administration of the medication. The rats were sacrificed after MRI scanning, and their hearts were harvested for pathological examination. The levels of serum biochemical indicators were measured by enzyme-linked immunosorbent assay (ELISA). CAVO significantly increased LV ejection fraction and overall myocardial strain parameters in LVR rats, while it decreased LV volume, mass, and serum levels of endothelial function indicators in LVR rats. In addition, pathological staining showed marked improvements in the hypertrophy, necrosis and interstitial fibrosis of cardiomyocytes. Through the regulation of myocardial vascular endothelial function, CAVO can significantly improve cardiac functions in LVR rats, delay the process of ventricular remodeling, and have a certain amount of protective effect on cardiac structure and function in rats.

Effect of Simvastatin on Ventricular Remodeling in Rats with Acute Myocardial Infarction through Transforming Growth Factor-Beta/SMAD Signaling Pathway

Effect of Simvastatin on Ventricular Remodeling in Rats with Acute Myocardial Infarction through Transforming Growth Factor-Beta/SMAD Signaling Pathway

A-kinase anchoring protein 5-ancored calcineurin regulates the remodeling of H9c2 cardiomyocytes exposed to hypoxia and reoxygenation

ObjectiveA-kinase anchoring protein 5 (AKAP5) is involved in ventricular remodeling in rats with heart failure after myocardial infarction; however, the specific mechanism is not clear. This study investigated whether AKAP5 anchors calcineurin (CaN) to regulate the remodeling of H9c2 cardiomyocytes. MethodsH9c2 cells were subjected to hypoxia stress for 3 h and reoxygenation for 24 h to create a hypoxia-reoxygenation (H/R) model. These cells were divided into three groups: H/R (model), empty vector +H/R (NC), and siRNA-AKAP5+H/R (siRNA-AKAP5) groups. The non-H/R H9c2 cells were used as normal controls. Western blotting was used to detect cardiac hypertrophy-related protein expression in the cells, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta myosin heavy chain (β-MHC), and phosphorylated nuclear factor of activated T-cell 3 (p-NFATc3). Phalloidin staining was used to label the cytoskeleton and the cell area in different groups was measured. Immunofluorescence staining and coimmunoprecipitation were used to study the relationship between AKAP5 and CaN. H9c2 cells pretreated with the CaN inhibitor FK506 were used to further verify the relationship between AKAP5 and CaN. ResultsIn the siRNA-AKAP5+H/R group, the expression level of cardiac hypertrophy-related proteins (ANP, BNP, and β-MHC) and CaN and the area of cardiomyocytes were significantly increased, while the p-NFATc3/NFATc3 ratio was decreased in H9c2H/R cells. AKAP5 and CaN proteins were colocalized and interacted in the cells. The CaN inhibitor significantly suppressed the expression of CaN, increased the p-NFATc3/NFATc3 ratio, and reduced the expression levels of ANP, BNP, and β-MHC proteins in the cells with low AKAP5 expression. ConclusionsAKAP5 downregulation aggravated the remodeling of cardiomyocytes after H/R. AKAP5 may anchor CaN to form a complex, which in turn activates NFATc3 dephosphorylation and expression of hypertrophy-related proteins.

S-adenosyl-L-methionine improves ventricular remodeling after myocardial infarction by regulating angiogenesis and fibrosis

Purpose: To investigate the effect of S-adenosyl-L-methionine (SAM) on angiogenesis and fibrosis in the heart of rats with myocardial infarction (MI), and to determine the mechanism of action.Methods: Sprague Dawley rats with MI received SAM treatment (15 mg/kg) intraperitoneally. The cumulative survival (%) of rats was recorded to determine their rate of survival. Hematoxylin-eosin staining, echocardiography, and hemodynamics were also performed. In addition, the effects of SAM vascular regeneration in the rats were analyzed by determining the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hypoxia-inducible factor 1-α (HIF1-α) in rats.Results: The 8-week survival rate of the MI group was significantly lower than that of the sham group, while SAM significantly improved the survival rate of the rats. In addition, SAM improved the contractile and diastolic heart function in the rats and also increased the ventricular pressure change. Furthermore, SAM elevated the expressions of VEGF, bFGF and HIF1-α in rat myocardium and serum. In myocardial tissues of SAM-treated rats, the expressions of collagen I, collagen III and α-sma were reduced, indicating that SAM inhibited myocardial fibrosis. In addition, SAM promoted cardiac angiogenesis by activating Jagged1/Notch1 signaling pathway.Conclusion: SAM promotes angiogenesis of the myocardium by activating Jagged1/Notch1 signaling pathway and inhibiting fibrosis in rat myocardium. Therefore, SAM effectively inhibits ventricular remodeling in rats after MI, thereby improving the rats’ heart structure and function. The results may provide new targets for the treatment of myocardial infarction.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal microRNA-29b-3p Promotes Angiogenesis and Ventricular Remodeling in Rats with Myocardial Infarction by Targeting ADAMTS16.

An increasing amount of evidence has suggested that microRNA (miR) plays a role in myocardial infarction (MI). Our study aimed to discuss the impact of exosomal miR-29b-3p in MI by regulating A Disintegrin and Metalloproteinase with Thrombospondin Motifs 16 (ADAMTS16). Exosomes were extracted from bone marrow mesenchymal stem cells (BMSCs). In a rat model of MI, myocardial angiogenesis and ventricular remodeling-related factors, as well as myocardial fibrosis, collagen volume fraction (CVF), capillary density, level of vascular endothelial growth factor (VEGF), and apoptosis of cardiomyocytes, were tested. ADAMTS16 and miR-29b-3p levels in the myocardial tissue of MI rats were tested. miR-29b-3p expression was decreased and ADAMTS16 expression was increased in the myocardial tissue of MI rats. ADAMTS16 was a target gene of miR-29b-3p. Upregulated miR-29b-3p delivered by BMSC-derived exosomes improved myocardial angiogenesis and ventricular remodeling, reduced myocardial fibrosis and CVF, increased capillary density and VEGF expression, and suppressed apoptosis of cardiomyocytes in MI rats. ADAMTS16 overexpression accelerated MI in rats, and ADAMTS16 upregulation reversed the protective effects of miR-29b-3p upregulation on MI rats. Our study provides evidence that upregulated miR-29b-3p delivered by BMSC-secreted exosomes can improve myocardial angiogenesis and ventricular remodeling in rats with MI by targeting ADAMTS16.

VPO1/HOCl/ERK pathway mediates the right ventricular remodeling in rats with hypoxic pulmonary hypertension

Right ventricular (RV) remodeling is a major feature of pulmonary arterial hypertension (PAH). Vascular peroxidase 1 (VPO1) is reported to participate in the process of PAH. This study aims to explore whether VPO1 contributes to hypoxia-induced cardiac hypertrophy and the underlying mechanisms. SD rats were exposure to continuous hypoxia (10% O2) for 3 weeks, which showed RV hypertrophy (increases in the ratio of RV weight to tibia length, cardiac cell size and hypertrophic markers), concomitant with upregulation of VPO1, elevation in hypochlorous acid (HOCl) production and ERK phosphorylation. In hypoxia (3% O2)-induced hypertrophic H9c2 cells, similar characteristics of cardiac hypertrophy to that of hypoxia-treated rats were observed. Administration of VPO1 siRNA or NaHS (the HOCl inhibitor) suppressed HOCl production, ERK phosphorylation, and cardiac hypertrophy. Replacement of hypoxia with NaClO (exogenous HOCl) could also induce cardiac cell hypertrophy and activate ERK signaling pathway. In addition, hypoxia-induced cardiac hypertrophy could be blocked by PD98059 (the ERK-specific inhibitor). Based on these observations, we conclude that VPO1 promotes RV remodeling in PAH rats through catalyzing HOCl production, leading to the activation of ERK signaling. Thus, VPO1 may have the potential as a therapeutic target for PAH.

Grape seed proanthocyanidin alleviates left ventricular remodeling by regulating systolic pressure, oxidative stress and vasoactive substances in spontaneously hypertensive rats

Purpose: To study the effect of grape seed proanthocyanidin (GSP) on left ventricular remodeling in spontaneously hypertensive rats, and the underlying mechanism.&#x0D; Methods: Spontaneously hypertensive rats were randomly divided into two groups, with 12 rats per group. One group was injected with GSP. Systolic pressure in each group was measured at baseline (before treatment), and at 3, 6 and 9 weeks after treatment. Whole heart index and left heart index were calculated. Histopathological changes in myocardium and left ventricular posterior wall thickness of rats in each group were measured. The cross-sectional area of myocardial cells and myocardial collagen volume fraction were assessed. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), nitric oxide (NO), renin, angiotensin II (Ang II), endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) in each group of rats were assayed.&#x0D; Results: Compared with the spontaneous hypertension group, whole heart mass index, left heart mass index, left ventricular posterior wall thickness, cross sectional area of myocardial cells, myocardial collagen volume fraction, and levels of MDA, renin, Ang II and ET-1 in GSP group were significantly decreased, while the expression levels of SOD, CAT, NO and eNOS were markedly increased in GSP group (p &lt; 0.05). Cell hypertrophy in the GSP group was significantly mitigated, when compared with that in the spontaneous hypertension group.&#x0D; Conclusion: GSP mitigates left ventricular remodeling in rats by reducing systolic blood pressure, improving antioxidant capacity and regulating levels of vasoactive substances, thus suggesting its potential for the management of hypertension.

Targeting mitochondrial dysfunction with elamipretide.

Although currently employed therapies for heart failure decrease overall mortality and improve patient quality of life temporarily, the disease is known to progress even for patients who receive all guideline-recommended therapies. This indicates that our concise understanding of heart failure and of disease progression is incomplete, and there is a need for new interventions that may augment, or even supplant, currently available options. A literature review reveals that an exciting, novel area of current research is focused on mitochondria, which are uniquely juxtaposed at the sites of both generation of high-energy molecules and initiation of programmed cell death. Elamipretide is being studied both to maintain cellular biogenetics and prevent reactive oxygen species-induced cell damage by targeting and stabilizing the cardiolipin-cytochrome c supercomplex. Thus far, elamipretide has been shown to increase left ventricular ejection fraction in dog models of heart failure with reduced ejection fraction and to prevent left ventricular remodeling in rats. In early-phase clinical trials, elamipretide administration has not resulted in any severe adverse events, and it has shown promising improvements in cardiac hemodynamics at highest doses. Nonetheless, additional studies are necessary to describe the long-term safety and efficacy of elamipretide.

Upregulated microRNA-210-3p improves sevoflurane-induced protective effect on ventricular remodeling in rats with myocardial infarction by inhibiting ADCY9

Myocardial infarction (MI) is a significant cause of death and disability, and sevoflurane (sevo) can protect myocardium in clinic. We aim to assess the effects of miR-210-3p on MI rats undergoing sevo treatment with the involvement of adenylyl cyclase type 9 (ADCY9). Rat MI models were constructed by ligation of the left anterior descending, and the modeled rats were respectively treated with sevo, miR-210-3p agomir, antagomir, or overexpressed ADCY9. Then, miR-210-3p and ADCY9 expression, cardiac function, myocardial injury and fibrosis, and cardiomyocyte apoptosis in rats were evaluated. Target relation between miR-210-3p and ADCY9 was detected. miR-210-3p was downregulated while ADCY9 was upregulated in MI rats. Sevo was able to promote cardiac function and attenuate myocardial injury and fibrosis, as well as cardiomyocyte apoptosis in MI rats. These effects of sevo were strengthened by miR-210-3p elevation but abolished by miR-210-3p inhibition in MI rats. The role of elevated miR-210-3p in MI rats was reversed by overexpression of ADCY9. Upregulated miR-210-3p improves sevo-induced protective effect on ventricular remodeling in rats with MI through inhibiting ADCY9.

Velvet Antler Ameliorates Cardiac Function by Restoring Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats With Heart Failure After Myocardial Infarction.

Objective: Velvet antler (VA; cornu cervi pantotrichum), a well-known traditional Chinese medicine, has been shown to exert cardioprotective effects. The purpose of this study was to investigate the effect of VA on heart failure (HF) caused by ischemia-reperfusion, and explore its possible mechanism from the regulation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 alpha (SERCA2a). Methods: A rat model of HF was established by ligating the left anterior descending coronary artery of male Sprague–Dawley rats (n = 88). One week after surgery, VA (200, 400, or 800 mg/[kg day−1]) or enalapril (1 mg/[kg day−1]) was administered daily for the next 4 weeks. Heart function was detected by echocardiography and histopathological analysis. The serum BNP level was measured by ELISA, and the expression of SERCA2a, PLB, PLB-Ser16, and PKA was determined by western blotting. SERCA2a and PLB mRNA levels were determined by real-time quantitative PCR. Results: Compared with the sham group, cardiac function in the HF group, including the serum BNP level, heart mass index, myocardial collagen deposition, and left ventricular ejection fraction, was markedly reduced; however, these changes could be reversed by VA treatment. In addition, VA (200 mg/[kg·d−1]) inhibited the decrease of SERCA2a and PLB mRNA levels and SERCA2a, PLB, PLB-Ser16, and PKA protein expression and restored the activity of SERCA2a and PKA. Enalapril affected only PLB protein expression. Conclusion: VA can improve myocardial fibrosis and ventricular remodeling in rats, thereby helping to restore cardiac function. The underlying mechanism may be related to the upregulation of the expression and activation of PKA and PLB and the restoration of the expression and activity of SERCA2a.

Aerobic exercise improves cardiac function in rats with chronic heart failure through inhibition of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1).

BackgroundTo explore the beneficial effects and underlying mechanisms of aerobic exercise on chronic heart failure (CHF).MethodsA CHF rat model was induced via left anterior descending coronary artery ligation. Four weeks post-surgery, CHF rats received aerobic exercise training over an 8-week period and cardiac function indexes including xxx were analyzed. To investigate the mechanisms involved in the aerobic exercise-induced benefits on CHF, overexpression of the long non-coding RNA MALAT1 was examined both in vivo and in vitro. Furthermore, the interaction between MALAT1 and the microRNA miR-150-5p and the downstream PI3K/Akt signaling pathway was investigated.ResultsCompared to the control group, the CHF rats showed evidence of left ventricular dysfunction including aggravated cardiac function indexes and lung to body weight ratio. The Masson staining demonstrated a significant degree of blue-stained fibrotic myocardial tissue in CHF rats compared to control rats. Furthermore, the levels of collagen I and collagen II were also markedly increased in CHF rats. Aerobic exercise improved cardiac function and left ventricular remodeling in rats with CHF. There was a significant reduction in the levels of the reactive oxygen species (ROS), inflammatory cytokines including TNF-α, IL-6, and IL-1β, and inflammatory mediums containing the matrix metalloproteinases (MMPs) MMP-2 and MMP-9. Moreover, CHF rats receiving aerobic exercise showed decreased myocardial apoptosis and increased expression of autophagy-related proteins including beclin-1 and LC3B-II. Overexpression of the lncRNA MALAT1 eliminated all the beneficial effects related to aerobic exercise in CHF rats. Subsequent investigations demonstrated that miR-150-5p expression was up-regulated in CHF-Tr rats and down-regulated in CHF-Tr-MALAT1 rats. Furthermore, the downstream PI3K/Akt signaling pathway was re-activated in CHF-Tr-MALAT1 rats. In vitro experiments revealed that overexpression of MALAT1 reduced the miR-150-5p levels, resulting in increased cellular apoptosis and less autophagy. In addition, overexpression of MALAT1 suppressed the downstream PI3K/Akt signaling pathway. Restoring miR-150-5p level with a miR-150-5p mimic decreased the cellular apoptosis and increased autophagy, and the downstream PI3K/Akt signaling pathway was re-activated.ConclusionsAerobic exercise improved cardiac function through inhibition of the lncRNA MALAT1 in CHF, and the potential mechanisms may be mediated via the miR-150-5p/PI3K/Akt signaling pathway.

Pathogenetic features of morphodensitometric characteristics of cardiomyocytes and marker profile of the left ventricular remodeling in rats with experimental intermittent hypoxia of different duration

Myocardial remodeling is considered as a three-component complex process, including cardiomyocyte hypertrophy, their apoptosis, interstitial and perivascular fibrosis. At the same time, the nature of remodeling and the direction of restructuring in the myocardium depend on the prevalence of one of these processes, the degree of their severity and the impact duration. Therefore, to understand the effect of short- and long-term intermittent hypoxia on the direction of myocardial remodeling and its type, the aim of this study was to determine the pathogenetic features of the morphodensitometric characteristics of cardiomyocytes and the marker profile of left ventricular myocardial remodeling in the rats with experimental intermittent hypoxia durated 15 and 60 days.Material and methods. A total of 30 male Wistar rats aging 6-10 months were used for the experiment and assigned to 3 experimental groups of 10 animals each: control; rats exposed to 15-day hypoxia; rats exposed to 60-day hypoxia. The object of the study was the left ventricular myocardium. The number of nuclei in an image, their average linear size and density (the ratio of the total area of nuclei to the area of the cytoplasm), and the concentration of RNA in the nucleus and cytoplasm were measured in the sections stained by Einarson via morphodensitometric method. An immunofluorescence method was used to study the content of immunoreactive material to markers of remodeling (cardiotrophin-1, type I collagen, titin, annexin V). As a result of the study, it was found that intermittent hypoxia led to a decrease in the number of nuclei in cardiomyocytes in both experimental groups compared to the control. Such changes in the number of nuclei were accompanied by significantly larger nuclear size compared to the control (in rats with 15-day hypoxia by 52.9 %, in rats with 60-day hypoxia - by 153.4 %) and a decrease in the density of nuclei in relation to the cytoplasm by 19.5 % and 21.2 %, respectively. In both groups, a significantly lower control concentration of RNA in the nuclei of cardiomyocytes was found alongside with an increase in their area. Such changes were accompanied by a significantly higher concentration of RNA by 23.2 % in the cytoplasm in case of long-term intermittent hypoxia. The marker profile of remodeling parameters in rats exposed to 15-day hypoxia was characterized by a higher content of cardiotrophin-1 and titin by 11.5 % and 23.1 %, respectively, as compared to the control. The content of type I collagen was 19.9 % higher, while the content of annexin V did not change significantly. In rats with long-term 60-day hypoxia, the content of cardiotrophin-1 was higher by 73.6 %, titin - by 124.9 %, type I collagen - by 41.9 %, and annexin V - by 95.9 % in comparison to the control. When calculating the titin / collagen ratio in rats based on their content, a significant increase in myocardial stiffness was determined in the 60-day hypoxia group which was 1.44, while it was0.91 in the control, and in rats with 15-day short-term hypoxia – 0.93.Conclusions. Intermittent hypoxic effects, regardless of duration, result in morpho-structural rearrangements of the myocardium, are characterized by an increase in viscoelastic mechanical properties and the development of hypertrophy, but with an increase in the duration of exposure (60 days) – by an additional formation of interstitial fibrosis and apoptosis of cardiomyocytes. Short-term hypoxia forms a hypertrophic type of myocardial remodeling with a decrease in the number of nuclei alongside with an increase in their size and a moderate decrease in RNA concentration. The marker profile of remodeling changes in a physiological manner and is characterized by an increase in the content of cardiotrophin-1, type I collagen and titin, while maintaining the titin / collagen ratio and normal apoptotic rate. Long-term hypoxia causes a fibro-apoptotic type of pathological myocardial remodeling including an almost two-fold decrease in the number of nuclei with an increase in their size and a decrease in RNA concentration. The marker profile of remodeling is characterized by an increase in all 4 components, a significant increase in the titin / collagen ratio and high apoptotic rate of cardiomyocytes.

Transplantation of viable mitochondria improves right ventricular performance and pulmonary artery remodeling in rats with pulmonary arterial hypertension

ObjectiveBecause mitochondrial dysfunction is a key factor in the progression of pulmonary hypertension, this study tested the hypothesis that transplantation of exogenous viable mitochondria can reverse pulmonary artery remodeling and restore right ventricular performance in pulmonary hypertension. MethodsPulmonary hypertension was induced by parenteral injection of monocrotaline (60 mg/kg) and creation of a left-to-right shunt aortocaval fistula in rats. Three weeks after creation of fistula, the animals were randomly assigned to receive intravenous delivery of placebo solution or allogeneic mitochondria once weekly for 3 consecutive weeks. Mitochondria (100 μg) were isolated from the freshly harvested soleus muscles of naïve rats. Transthoracic echocardiography was performed at 3 weeks after mitochondrial delivery. ResultsEx vivo heart-lung block images acquired by an IVIS Spectrum (PerkinElmer, Waltham, Mass) imaging system confirmed the enhancement of MitoTracker (Invitrogen, Carlsbad, Calif) fluorescence in the pulmonary arteries. Mitochondria transplantation significantly increased lung tissue adenosine triphosphate concentrations and improved right ventricular performance, as evidenced by a reduction in serum levels of B-type natriuretic peptide and ventricular diameter. Right ventricular mass and wall thickness were restored in the mitochondrial group. In the pulmonary arteries of rats that received mitochondrial treatment, vascular smooth muscle cells expressed higher levels of α-smooth muscle actin and smooth muscle myosin heavy chain II, indicating the maintenance of the nonproliferative, contractile phenotype. The hyper-reactivity of isolated pulmonary arteries to α-adrenergic stimulation was also attenuated after mitochondrial transplantation. ConclusionsTransplantation of viable mitochondria can restore the contractile phenotype and vasoreactivity of the pulmonary artery, thereby reducing the afterload and right ventricular remodeling in rats with established pulmonary hypertension. The improvement in overall right ventricular performance suggests that mitochondrial transplantation can be a revolutionary clinical therapeutic option for the management of pulmonary hypertension.

Guanxinshutong capsule ameliorates cardiac function and architecture following myocardial injury by modulating ventricular remodeling in rats

Guanxinshutong capsule (GXST), which consists of five traditional Chinese medicines, has been used for a long time in China for the treatment of cardiovascular diseases, such as coronary artery disease and myocardial infarction. However, the effects on GXST on myocardial injury (MI) have not been studied in detail. In these experiments, we found that GXST administration decreased MI-associated ventricular remodeling (VR) with a reduction in interventricular septal thickness in diastole (IVSd), left ventricular posterior wall diameter in systole (LVPWs), and left ventricular posterior wall diameter in diastole (LVPWd) to ameliorate cardiac function and architecture, as measured by echocardiography. Furthermore, histological analysis showed that GXST could ameliorate pathological alterations in the myocardium. And Sirius red staining, wheat germ agglutinin staining and inflammation-related immunohistochemistry results showed that GXST ameliorated the fibrosis areas, cardiac hypertrophy and inflammation (IL-6 and TNF-α). In addition, GXST upregulated intercellular junction proteins (N-cad and Cx-43) and downregulated the angiogenesis-related proteins (PDGF and VEGFA), myocardial fibrosis-related proteins (TGF-β1), and matrix metalloproteinase (MMP-2 and MMP-9). We also found that GXST medium-dose group (1 g/kg/d) dosage was the most efficacious. In conclusion, GXST protected cardiac tissues against MI by reducing VR, thus indicating the potential application of GXST in the treatment of MI.

β1-Blocker improves survival and ventricular remodelling in rats with lethal crush injury.

Crush injury/crush syndrome (CI/CS) is the second most common cause of death during earthquakes. Most studies of CI/CS have mainly focused on kidney injury after decompression. Few studies have focused on myocardial injury caused by crush injury and its potential mechanisms. We first verified cardiomyocyte injury during compression in rats with a crush injury. The survival rate, electrocardiographic results, histological results, catecholamine changes and cardiac β1-AR expression were evaluated. Next, we explored the effects of pretreatment with a selective β1-blocker (bisoprolol) with or without fluid resuscitation on rats with a crush injury. In addition to evaluating the survival rates, biochemical and histological analyses and echocardiographic measurements were also performed. Reduced heart rates, elevated ST segments, and tall-peaked T waves were observed in the rats with a crush injury. The changes in the myocardial enzymes and pathological results demonstrated that myocardial damage occurred during compression in rats with a crush injury. The levels of the catecholamine norepinephrine in both the serum and myocardial tissue were elevated during compression. Pretreatment with a selective β1-blocker combined with fluid resuscitation significantly improved the survival rates of the rats with lethal crush injury. The myocardial enzymes and pathological results showed that the combined therapy decreased myocardial damage. The echocardiography measurements showed that the rats that received the combined therapy exhibited decreased left ventricular mass (LVM), left ventricular volume at end-systole (LVVs) and left ventricular internal diameter (LVID) compared with the rats with a crush injury. Our findings demonstrated the presence of myocardial injury in the early stage of compression in rats with a crush injury. Pretreatment with a β1-blocker (bisoprolol) with fluid resuscitation significantly reduced mortality, decreased myocardial tissue damage, and improved ventricular remodelling in rats with a lethal crush injury.